Long-term treatment with TKIs is of special concern in pediatric patients (pts) with CML as these drugs -beside their specific inhibition of the BCR-ABL oncogene- exert multiple off-target effects. Among these the precise influence on the longitudinal growth and the reproductive endocrine system –being of particular interest in growing organisms– is still not clarified. We therefore investigated in blood serum the growth hormone-related parameter insulin-like growth factor-binding protein 3 (IGFBP3) as well as testosterone (Testo) and inhibin B (InB) in an animal model of juvenile rats and pediatric pts with CML chronically exposed to TKIs.
In 23 pts (13 males; age: 7.8 – 18.9 years, median: 12.8 yrs) with CML in chronic phase being enrolled into the pediatric trial CML-Paed II (ClinicalTrials.gov identifier NCT00445822) blood serum was collected at three months intervals in the morning and sent in for central analysis at the study reference laboratory. Pts were receiving standardized imatinib (IMA) treatment (260–300 mg/sqm) for 3–58 months (median: 18 months).
In addition, in an animal model 4 week-old male Wistar rats were cohorted (controls, groups A, B, C; each n=10 animals) and exposed over 10 weeks to either IMA, dasatinib (DASA), or bosutinib (BOSU) at varying concentrations via the drinking water (controls: water only; IMA: A) 1mM, B) 2 mM, C) 2 mM at three days per week [Monday–Wednesday]; DASA and BOSU, respectively: A) 50 μM, B) 100 μM, C) 100 μM at 3 days per week). Blood was collected at prepubertal age (6 weeks old), pubertal age (8 weeks old), and at adult age (14 weeks old), respectively. Serum levels of IGFBP3 (in all pts), Testo, and InB (in males) were measured by commercially available ELISA in humans and rats.
IGFBP3 levels were determined in 21 pediatric pts and were found still within the normal, however, uniformly in the very low range (Z-score: −1 to −2) compared to age-matched reference values (p<0.001). In male pts serum levels of Testo (n=13) and InB (n=11) were within normal age-related reference ranges according to Tanner puberty score. No clear pattern of rising or falling Testo or InB levels during TKI treatment could be observed.
In rats, compared to controls serum IGFBP3 levels (range: 19–40 ng/ml) were highly significantly lowered (range: 7–16 ng/ml; p-values <0.01 - <0.001) for all TKIs tested, at all concentrations applied, and at all ages when investigated. Also longitudinal bone growth retardation occurred in these animals as described elsewhere (Tauer JT et al. 2011 ASH Abstract #1597; Tauer JT et al. 2012 EHA Abstract #1256). Keeping in mind that the number of animals tested at each age group was rather small, Testo levels under IMA exposure tended to be non-significantly lowered at postpubertal age compared to controls while no significant differences were found under DASA and BOSU exposure. Also for all TKIs tested in rats, InB serum levels did not significantly differ compared to controls.
Impairment of longitudinal growth in pediatric pts on TKIs has been described in several reports as well as in animal models (Suttorp M, et al 2012). Besides direct off-target effects on differentiation and metabolic activity of bone resorbing and forming cells (osteoclasts and osteoblasts) involved in bone remodelling, TKI treatment probably results also in lowered growth hormone secretion. Based on these first data from a small cohort of pts it seems reasonable to monitor growth hormone-related parameters like IGFBP3 regularly in pediatric pts with CML. Our data do not confirm a general inhibitory effect on Testo and InB blood levels neither in pts nor in rats. Thus, testicular toxicity due to TKI seems unlikely, however, clinically individual cases with impaired gonadal function and/or late-onset puberty remain to be investigated.
This investigation was supported by grants DFG SU122–3/1, Peter Escher Foundation (Leipzig), and Foerderkreis Sonnenstrahl e.V. (Dresden).
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.